Influenza disseminates each year into local and global epidemics of respiratory illness and death. Epidemics are fostered by the rapid introduction of new and transmissible influenza strains (mutated or recombinant) into susceptible human populations. Influenza is a mucosal disease which targets distinct anatomic sites, the upper and lower respiratory mucosae, each of which may be an independent target for vaccine-mediated protection. Transmission may occur from contact with large particle fomites on hands (to conjunctiva and nose), with moderate size particles from the upper respiratory tract (to nose and trachea), and with very small particles from deep in the lung (to alveoli in lung). Viremia with infectious virus is less common. Viral RNA detected in blood, e.g., with severe avian H5N1 disease, likely derives from a high viral burden in the lung. Mechanisms of natural and vaccine-induced immunity against primary infection include 1) virus- specific mucosal (esp. secretory IgA [S-IgA]) and systemic (esp. IgG) antibodies from memory B cells, 2) mucosal innate immune factors to retard viral binding and infection of epithelium, and 3) T cells. Cytotoxic CD8+ T cells [CTL] may be most important is resolving established infection, and CD4+ T cells regulate both CD8+ T and B cells. Based on viral selectivity for nasal, tracheal and alveolar sialic acid receptors, human influenza strains may infect both the upper and lower airways, whereas avian strains may more selectively infect the lower. Morbidity and mortality are related more to infection of the lower respiratory tract. Such site- specific infection and complications stress the need to evaluate compartment-specific defenses. Live attenuated nasal vaccine provides comparable or better protection than inactivated parenteral vaccines vs. influenza disease in children and adults. However, humoral responses, which are most important in defense against initial influenza infection, to each vaccine differ at systemic and mucosal sites. Compared with inactivated parenteral vaccine, live attenuated nasal vaccine is reported to elicit lower levels of influenza- specific IgG in blood and somewhat higher levels of specific mucosal S-IgA in the nasopharynx. IgG likely contributes to protection in the lung, and specific S-IgA to both upper and lower respiratory defenses. We propose to characterize functional antiviral activities elicited by these 2 anatomically-diverse vaccines in humans in distinct sites relevant to control of influenza, providing tools essential for predicting protective responses, including heterotypic systemic and mucosal responses, especially in the lung. [unreadable] [unreadable] [unreadable] [unreadable]